| Radiation therapy is extensively used in patients with cancer however,radiation-induced injury remains the overwhelming barrier to patients,which adversely interrupt treatment and can even lead to death.In addition,radiation exposure in a mass casualty setting is a serious military and public health concern.Exposure to a high dose of irradiation in a short time is associated with bone marrow toxicity(haematopoietic syndrome)and gastrointestinal(GI)toxicity(GI syndrome).Therefore,it is urgent to uncover potential risk factors that deteriorate the prognosis of cancer patients after radiotherapy as well as the contemporary approaches for prevention radiation-induced inj ury.Here,we explored the effect of acute P80 consumption on the worsening of irradiation-induced GI toxicity.In addition,we evaluated the therapeutic potential and mechanisms of butyrate and valeric acid in a rodent model.Part 1.Butyrate fights against dietary emulsifier-aggravated irradiation injury.Radiation therapy is widely used to treat cancer,while even precision radiotherapy may be accompanied by a series of side effects,especially GI.Intestinal microbiota can be manipulated to fight against many diseases.Here,we investigated whether polysorbate 80(P80),an emulsifier,exacerbated irradiation-induced intestinal injury.High throughput sequencing analysis indicated that P80 consumption altered the abundance and composition of gut microbiota and worsened TAI-induced GI tract injury.P80 consumption reduced the survival rate,increased the weight loss,shortened the colons length,decreased the number of intact intestinal villi and goblet cells in mice following TAI.We also obtained a reduction in the expression of all four integrity-related genes in the P80-challenged animals.Oral gavage of P80 shaped the intestinal bacterial composition,and transplantation of fecal microbes from P80-treated mice rendered normal animals more susceptible to irradiation.HPLC assay showed that the level of butyrate was reduced in the feces of irradiated animals and was further reduced after subjected to P80 exposure.Replenishment of butyrate protected against P80-exacerbated injury mediated by irradiation.In addition,butyrate treatment up-regulated Mgam,Glut2 and Sglt1 expression,which were essential genes for digestion and energy absorption.Importantly,butyrate prevented P80-aggravated disturbance of intestinal bacterial composition in irradiated animals.Collectively,our findings suggest that acute consumption of food additives renders animals more susceptible to irradiation injury,which can be attenuated by an enteric microbial fermentation metabolite,butyrate,a potential therapy for irradiation injury.Part 2.Valeric acid protects against radiation-induced haematopoietic syndrome and GI toxicity.Here,we investigated valeric acid,a metabolite of gut microbiota,attenuated radiation-induced haematopoietic syndrome and GI syndrome.Male C57BL/6J mice were separated into three groups,"control group","radiation alone group" and "radiation and valeric acid treated group".HPLC assay showed that the level of valeric acid was reduced in the feces of irradiated animals,which could be elevated in feces from mice received the fecal microbiota from normal mice.After 7.2 Gy total body irradiation(TBI),valeric acid treatment retained the reduced survival rate of irradiated mice,elevated the volume of dissected spleens and thymuses,reduced IL-6 and TNF-? in peripheral blood.After total abdomen irradiation(TAI),valeric acid administration retained the reduced body weight of irradiated mice,increased the number of goblet cells,up-regulated the integrity-related genes,as well as reduced IL-6 and TNF-? at transcriptional level and translational level in intestines.High throughput sequencing analysis indicated that oral gavage of valeric acid has no effect on the abundance of intestinal microbiota,but prevents TAI-educated intestinal bacterial composition.iTRAQ was performed to analyse the protein expression profile in the study,and we chose Keratin 1(KRT 1)to further study the mechanism behind the protective effect of valeric acid on radiation-induced injury.Realtime-PCR assay revealed that valeric acid treatment elevated KRT 1 at transcriptional level.As expected,valeric acid promoted the irradiation-inhibited proliferation of HIEC-6 cells in vitro,however,valeric acid failed to work when KRT 1 was knock down.Collectively,our findings suggest that valeric acid attenuats radiation-induced haematopoietic syndrome and GI toxicity involving KRT 1. |
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